1. Field of the Invention
This invention relates to a device for dispensing medication in the respiratory tract, and more particularly to a breath-activated device with provision for open and closed-mouth techniques, electronic measurement and control, and electro-mechanical activation.
2. Background
Asthma is a disease that is a growing epidemic in this country and affects 14.6 million Americans, including 5 million children. (Cowley G., & Underwood A., Why Ebonie Can't Breathe, Newsweek, May 26, 1997, 129(21), 58-64). According to the American Lung Association, the number of sufferers has risen by 61 percent since the early 1980's. Id. The death toll from asthma has also nearly doubled, to a tragic 5000 per year. Id. These statistics are appalling considering that today, physicians have many more types of medications available for treatment.
The majority of medications for asthma treatment are intended for delivery to the lung. In this way, the drug can most quickly reverse the acute breathing problem that asthma causes to the sufferer. Delivery of medication directly to the lung also allows use of less drug, minimizing systemic side effects, since only the lung is affected by the disease.
Techniques of medication delivery to the lungs for asthma sufferers have a long history and have seen many improvements. However, significant disadvantages remain in the delivery systems in use today. The nineteenth century saw the invention and use of the glass bulb nebulizer. (Hampson N. B., Mueller M. P., Reduction In-Patient Timing Errors Using A Breath-Activated Metered Dose Inhaler, Chest, August 1994, 106(2), 462-465). At the turn of the century, cigarettes laced with atropine were used. Id. The first pressure metered dose inhaler (MDI) was introduced in 1956. (Newman S. P., Weisz A. W., Talaee N., Clarke S. W., Improvement Of Drug Delivery With A Breath-Activated Pressurized Aerosol For Patients With Poor Inhaler Technique, Thorax, 1991, 4(46), 712-716). Though bulky, noisy and cumbersome to use, the first breath activated aerosol inhaler was introduced a number of years ago. Id. In an effort to improve medication delivery, spacer devices used with MDI's were introduced in the 1970's. (Iula, A. K., Flynn C. L., Delucca F., Comparative Study of The In Vitro Dose Delivery And Particle Size, Distribution, Characteristics Of An Azmacort Metered-Dose Inhaler In Combination With Four Different Spacer Devices, Current Therapeutic Research, August 1997, 58(8), 544-554).
Nebulizers have been the treatment mainstays for acute asthmatics in emergency departments. Nebulizers offer an advantage of delivering a higher dose of medication to the lung than MDI's (Newman S. P., Sted K. P., Resader S. J., Hooper G., Zierenberg B., Efficient Delivery To The Lungs Of Flunisolide Aerosol From A New Portable Hand-Held Multi-Dose Nebulizer, Journal of Pharm. Science, September 1996, 85(9), 960-964) and once set up, the nebulizer requires no training and minimal cooperation from the patient. With a nebulizer, there is also less deposition of medication in the oropharynx as compared to MDI's. (Battistini A., The Best Way To Apply Aerosol Therapy, Pediatric Med. Chir, March-April 1995, 17(2), 97-103). The deficiencies of nebulizers are that they are expensive, time consuming, bulky, non-portable, and usually AC current-dependent. A nebulizer also takes minutes to deliver its dose, and needs considerable time to set-up for that delivery. The output of nebulizers is device-dependent and there is significant inter-nebulizer and intra-nebulizer output variance. (National Institutes of Health: National Heart, Lung, and Blood Institute. Guidelines For The Diagnosis And Management Of Asthma, July 1997, Bethesda Md., NIH Publication No. 97-44051, 1-154).
Another treatment technique uses dry powder medication as a substitute for aerosol medication. Children and elderly patients often find dry powder inhalers easier to use than MDI's. (Newman S. P., Weisz A. W., Talaee N., Clarke S. W., Improvement Of Drug Delivery With A Breath-Activated Pressurized Aerosol For Patients With Poor Inhaler Technique, Thorax, 1991, 4(46), 712-716). It is reported that inhaler induced symptoms are lower with some dry powder inhalers (dry powder budesonide and turbutan) as compared to MDI's. (Pauwels R. A., Hargreave F. E., Camus P., Bukoski M., Stahl E., A 1-Year Study Of Turbohaler Vs Pressurized Metered Dose Inhaler In Asthmatic Patients, Chest, July 1996, 110(1), 53-57). Certain dry powder inhalers are also reported to deliver more drug to the lungs than an equivalent aerosol inhaler. (Borgstrom L., Derom E., Stahl E., Wahlin-Boll E., Pauwels R., The Inhalation Device Influences Lung Deposition And Bronchodilating Effect Of Terbutaline, American Journal of Respiratory and Critical Care Medicine, May 1996, 153(5), 1636-1640). However, another study reported that dry powder inhalers deliver only 10% of the inhaled medication dose to the lungs. (Taburet A. M., Schmidt B., Pharmacokinetic Optimisation Of Asthma Treatment, Pharmacokinetics, May 1994, 26(5), 396-418/published erratum in August 1994, 27(2), 149)
Currently, there are also breath activated dry powder inhalers on the market. Dry powder breath activated inhalers do not rely on coordination between activation and inhalation and therefore are easier for the patient to use. However, existing dry powder inhalers, including breath activated devices, have a number of disadvantages. The medication dose is lost if a patient exhales through the device. (National Institutes of Health: National Heart, Lung, and Blood Institute. Guidelines For The Diagnosis And Management Of Asthma, July 1997, Bethesda Md., NIH Publication No. 97-44051, 1-154). It is also necessary to inhale rapidly to use a dry powder inhaler properly. Id. Rapid inhalation may not be possible during an acute asthma exacerbation. (Boulet L. P., d'Amours P., Berube D., Rouleau M., Parent J. G., Pelletier C. & Touchette C., Update On Inhalation Therapy In Asthma And Obstructive Bronchopulmonary Diseases, Union Med. Canada, January 1994, 123(1), 23-31.sctn.). Thus, inspiratory flow may not be sufficient when medication is most needed.
Devices that do not rely on patient inhalation technique have an advantage in medication delivery for asthmatics. Spacers are one such device that is being promoted as a way to deliver aerosol from MDI's to the patient's lung without the need for skillful patient technique. Spacers used with MDI's also offer an advantage to MDI's alone in that less medication is deposited in the oropharynx, reducing local side effects. (National Institutes of Health: National Heart, Lung, and Blood Institute. Guidelines For The Diagnosis And Management Of Asthma, July 1997, Bethesda Md., NIH Publication No. 97-44051, 1-154). Larger volume spacers (&gt;600 cc) increase lung delivery in MDI's in patients with poor MDI technique. Id. This is due to the large droplets precipitating out in the spacer holding chambers prior to inspiration.
However, spacers also present certain disadvantages. Currently many spacers are being sold as universal for all aerosol canisters. A study found significant differences in the amount of drug available for inhalation when different spacers were used as inhalation aids with different drugs. (Barry P. W., O'Callaghan C., Do Multiple Actuations Of Salbutamol MDI Into A Spacer Device Reduce The Amount Of Drug Recovered In Respirable Range? European Respiratory Journal, September 1994, 7(9), 1707-1709). Spacers can also vary widely as to the amount of respirable dose delivered. (Iula, A. K., Flynn C. L., Delucca F., Comparative Study Of The In Vitro Dose Delivery And Particle Size, Distribution, Characteristics Of An Azmacort Metered-Dose Inhaler In Combination With Four Different Spacer Devices, Current Therapeutic Research, August 1997, 58(8), 544-554)
Another major problem with spacers is that multiple actuations into the volumetric spacer does not linearly increase the amount of drug available for inhalation. (Barry P. W., O'Callaghan C., Do Multiple Actuations Of Salbutamol MDI Into A Spacer Device Reduce The Amount Of Drug Recovered In Respirable Range? European Respiratory Journal, September 1994, 7(9), 1707-1709). The amount of medication within respirable particles decreases considerably following multiple activations into a spacer and with increasing residence times within the spacer before inhalation. (O'Callaghan C., Cant M., Robertson C., Deliver Beclomethasone Dipropionate From A Spacer Device: What Dose Is Available For Inhalation, Thorax, October 1994, 49(10), 961-964). Therefore, patients who pump repeatedly into a spacer during an acute attack to get additional medication, may mistakenly receive an insufficient dose.
Large volume spacers are also bulky, and medication export may be reduced in some devices after cleaning and by sanitization. (Bisgaard H., Anhoj J., Klug B., Berg E., A Non-Electrostatic Spacer For Aerosol Delivery, Arch. of Dic. Children, September 1995, 73(3), 226-230). Static electricity can also reduce spacer output. Id. Reduction in spacer output therefore may occur during conditions when asthma is exacerbated, such as cold dry weather.
For daily treatment of asthma symptoms, MDI's are the most common and widely prescribed medication delivery system for inhaled medications for asthmatics. Nearly all asthma sufferers depend on MDI's for disease control and symptomatic relief. Despite almost universal use of MDI's, a high percentage of users incorrectly employ MDI's.
The proper use of MDI's is complicated and requires the user/patient to perform the following steps: activation during early inspiration, adequate inspiratory flow, adequate breath holding and deep inhalation. (Goodman D. E., Israel E., Rosenberg M., Johnston R., Weiss St., Drazen J. M., The Influence Of Age, Diagnosis, And Gender On Proper Use of Metered-Dose Inhalers, American Journal of Respiratory and Critical Care Medicine, November 1994, 150(5 Part I), 1256-1261). The most frequent patient errors include: lack of coordination between activation and inspiration; absence of breath holding; and activation of the aerosol on more than one occasion during inspiration. (Boccuti L., Celano M., Geller R. J., Phillips K. M., Development Of A Scale To Measure Children's Metered Dose Inhaler And Spacer Technique, Annals of Allergy, Asthma and Immunology, September 1996, 77(3), 217-221). These errors adversely affect delivery of aerosol medication to the lower respiratory tract.
Improper inhaler technique and inadequate MDI design can lead to side effects from the inhaled medications. Corticosteroid inhalers are known to cause adrenal suppression in some asthmatic children. (Goldberg S., Algur N., Levi M., Brukheimer E., Hirsch H. J., Branski D., Kereem E., Adrenal Suppression Among Asthmatic Children Receiving Chronic Therapy With Inhaled Corticosteroid With And Without Spacer Device, Annals of Allergy, Asthma and Immunology, March 1996, 76(3), 234-238). This side effect is more common in patients inhaling directly from MDI's than those patients using a large volume spacer. Medication deposited in the oropharynx can lead to irritation, foul taste and thrush, which may cause the patient to avoid using the medication. Spacers/holding chambers decrease oropharyngeal deposition and reduce potential systemic absorption of inhaled corticosteroid preparations that have higher oral bioavailability. Without a spacer/holding chamber, approximately 80% of the dose from an MDI is swallowed. (National Institutes of Health: National Heart, Lung, and Blood Institute. Guidelines For The Diagnosis And Management Of Asthma, July 1997, Bethesda Md., NIH Publication No. 97-44051, 1-154). Spacer devices are reportedly useful in reducing local side effects in the oropharynx by decreasing deposits in the oropharynx by at least 90%.
One study reported that although MDI's are the most frequently prescribed type of inhaler, at least 50% of patients are unable to use these devices efficiently and 10 to 15% of those patients who can initially use the MDI efficiently later develop an inefficient technique. (Levitt M. A., Gambrioli E. F., Fink J. B., Comparative Trial Of Continuous Nebulization Versus Metered-Dose Inhaler In The Treatment Of Acute Bronchospasm, Annals of Emergency Medicine, September 1995, 26(3), 273-277). Another study showed that only 33.2% of adults and 26% of children used adequate technique (deep inspiration synchronized with inhaler activation, followed by breath holding for 5 seconds). (National Institutes of Health: National Heart, Lung, and Blood Institute. Guidelines For The Diagnosis And Management Of Asthma, July 1997, Bethesda Md., NIH Publication No. 97-44051, 1-154). It was also shown that almost one half of the patients studied did not activate the MDI canister at the start of inhalation.
The main factor related to the improper use of MDI's is absence of previous instruction. (Benjaponpitak S., Kraisaarin C., Direkwattanachai C., Sasissakunporn C., Incorrect Use Of Metered Dose Inhalers By Pediatric Residents, Journal of the Medical Association of Thailand, February 1996, 79(2), 122-126). Despite training by their physicians, several studies have demonstrated that many patients do not use MDI's or other inhaler devices correctly, and a simple training session is inadequate. Even with instruction, only 26% of instructed adults and 22.1% of instructed children used optimal technique. (Liard R., Zureik M., Aubier M., Korobaaaeff M., Henry C., Neukirch F., Misuse Of Pressurized Metered Dose Inhalers By Asthmatic Patients Treated In French Private Practice, Rev. Epidemiology Sante Publique, 1995, 43(3), 242-249). Unfortunately, instruction of MDI technique requires a significant time commitment and may not be feasible for all patients, especially those in an Emergency Department. (Selroos O., Lofross A. B., Pietinaalho A., Riska H., Comparison Of Terbutaline And Placebo From A Pressurized Metered Dose Inhaler And A Dry Powder Inhaler In A Subgroup Of Patients With Asthma, Thorax, December 1994, 49(12), 1228-1230). It has also been demonstrated that the motor/technical skill necessary to properly use an MDI inhaler can deteriorate over time. (HealthScan, Inc. Chances Are: Handbook of Clinical Probabilities in Asthma. 1997, 11(2) p. 1-6; First Quarter)
Physicians themselves have been shown to possess inadequate knowledge of the correct use of inhalers with all types of devices. (Rebuck D., Dzyngel B., Khan K., Kesten R. N., Chapman K. R., The Effect Of Structured Versus Conventional Inhaler Education In Medical Housestaff, Journal of Asthma, 1996, 33(6), 385-393). Postgraduate teaching programs leave physicians to acquire inhaler-handling skills informally in the context of day-to-day patient care. Id. Many medical personnel responsible for monitoring and instructing patients in optimal inhaler utilization do not possess rudimentary skills with these devices. (Hanania N. A., Wittman R., Kesten S., Chapman K. R., Medical Personnel's Knowledge Of And Ability To Use Inhaling Devices: Metered Dose Inhalers, Spacing Chambers, And Breath-Actuated Dry Powder Inhalers, Chest, January 1994, 105(1), 111-116). Of seven recommended steps for correct MDI use, residents, on average, correctly performed only 3.8 of these steps. (Amirav I., Goren A., Pawlowski N. A., What Do Pediatricians In Training Know About The Correct Use Of Inhalers And Spacer Devices? Journal of Allergy and Clinical Immunology, October 1994, 94(4), 669-675)
In one study, second-year pediatric residents improperly timed the activation of the MDI 49% of the time, activating the MDI canister before starting inhalation. (Benjaponpitak S., Kraisaarin C., Direkwattanachai C., Sasissakunporn C., Incorrect Use Of Metered Dose Inhalers By Pediatric Residents, Journal of the Medical Association of Thailand, February 1996, 79(2), 122-126). Seasoned physicians do not fare much better. In a survey, only 55% of faculty members correctly answered at least three of the seven steps necessary for proper inhaler technique, though all prescribed MDI's for their patients. (Hira H. S., Faulty Use Of Metered Dose Inhalers By Physicians, Journal of Assoc. of Physicians in India, July 1994, 42(7), 520, 524-525). While educational sessions may somewhat improve performance, education is not sufficient to guarantee perfect MDI technique. (Resnick D. J., Gold R. L., Lee-Wong M., Feldman B. R., Ramakrishnana R., Davis W. J., Annals of Allergy, Asthma Immunology, February 1996, 76(2), 145-148). A single training session using videotaped MDI demonstrations was shown to be inadequate in teaching pharmacists and pulmonary fellows to evaluate MDI technique. (Farr S. J., Rowe A. M., Rubsamen R., Taylor G., Aerosol Deposition In The Human Lung Following Administration From A Microprocessor Controlled Pressurized Metered Dose Inhaler, Thorax, June 1995, 50(6), 639-644)
If physicians and other health care personnel do not know how to use inhalers and have difficult learning proper technique, there is little chance that they can teach the patients proper technique.
In order to overcome some of the problems with poor MDI technique, aerosol breath activated inhalers are currently available. One such device is shown to require more rapid inspiration to activate than is optimal for deposition of medication into the lungs. (National Institutes of Health: National Heart, Lung, and Blood Institute. Guidelines For The Diagnosis And Management Of Asthma, July 1997, Bethesda Md., NIH Publication No. 97-44051, 1-154). The device also clicks loudly on actuation, and patients may reflexively stop inhalation upon hearing the click, preventing the full dose of medication from getting to the lungs. Id.
Optimal design of an MDI for a specific agent also requires precise calculation based on particle size and other physiochemical characteristics of the particular medication compound as it relates to the desired dose to be activated from the MDI sprayhead. The respirable dose is commonly defined as total dose with particle size&lt;5.8 micrometer. (Iula, A. K., Flynn C. L., Delucca F., Comparative Study Of The In Vitro Dose Delivery And Particle Size, Distribution, Characteristics Of An Azmacort Metered-Dose Inhaler In Combination With Four Different Spacer Devices, Current Therapeutic Research, August 1997, 58(8), 544-554)
One MDI study showed that firing with a medium inspiratory flow rate (90 liters/minute) and early in the cumulative inspired volume (&lt;300 ml) resulted in the highest lung deposition, at 18.6%. (Farr S. J., Rowe A. M., Rubsamen R., Taylor G., Aerosol Deposition In The Human Lung Following Administration From A Microprocessor Controlled Pressurized Metered Dose Inhaler, Thorax, June 1995, 50(6), 639-644). Unfortunately, 60% of asthma patients inhale at less than 60 liters/minute, and during acute attacks their flow rate may be less. (Newman S. P., Sted K. P., Resader S. J., Hooper G., Zierenberg B., Efficient Delivery To The Lungs Of Flunisolide Aerosol From A New Portable Hand-Held Multi-Dose Nebulizer, Journal of Pharm. Science, September 1996, 85(9), 960-964). Thus, an ideal device needs to be adaptable to fire even with very low flow rates, because it is at times like these that the asthma patient needs medication relief most desperately.
In addition to the problems identified above, one study found that insufficient hand strength was also a significant cause of the elderly not being able to use MDI's, which require the patient to apply manual pressure to the top and bottom of the device to activate it. (Gray S. L., Williams D. M., Pulliam C. C., Sirgo M. A., Bishop A. L., Donohue J. F., Characteristic Predicting Incorrect Metered Dose Inhaler Technique In Older Subjects, Archives of Internal Medicine, May 1996, 156(9), 984-988). An ideal MDI would require minimal hand strength so that both children and elderly could easily use the device.
Patients often run out of inhaler medication because they can not estimate how much medication remains in the canister. This is because they depend on inaccurate methods of estimation, such as shaking the inhalers and listening to the contents, estimating the weight of the canisters, and observing the size of the emissions.
Rapid serial reactivation of MDI's also reduces respirable dose by 15 to 18%. (Everard M. L., Devadason S. G., Summers Q. A., LeSouef P. N., Factors Affecting Total And "Respirable" Dose Delivered By Salbutamol Metered Dose Inhaler, Thorax, July 1995, 50(997), 746-749). An interval between actuation of at least 5 seconds is considered necessary to consistently deliver full doses. Id.
Additives in MDI's such as inert ingredients including propellant can cause bronchoconstriction in some patients with asthma. (Shaheen M. Z., Aayres J. G., Benincasa C., Incidence Of Acute Decreases In Peak Expiratory Flow Following The Use Of Metered Dose Inhalers In Asthmatic Patients, European Respiratory Journal, December 1994, 7(12), 2160-2164)
An open-mouth technique with MDI's, whereby the MDI is manually activated and coordinated with inhalation while the MDI is in proximity but not in direct contact with the patient's mouth, has been shown to lead to enhanced drug delivery to the lung compared to the conventional closed-mouth technique. (National Institutes of Health: National Heart, Lung, and Blood Institute. Guidelines For The Diagnosis And Management Of Asthma, July 1997, Bethesda Md., NIH Publication No. 97-44051, 1-154). None of the current breath activated inhalers are usable with open-mouth technique, however, and the open-mouth technique is difficult to master.
Thus, there are a number of disadvantages that are not addressed by current MDI's, spacers and breath-activated devices.